Comparison of concomitant mutational of type I/II/III BRAF mutation in colorectal cancer between Chinese and Western populations.
Authors: Yingying Huang, Li Zhongkang, Yun-Bo Zhao, Wenzhuo Jia, Jun Du, Gang Zhao, Guoju Wu
Journal: Journal of Clinical Oncology (2023)

e15634 Background: BRAF V600E CRC had a relatively poor prognosis.The efficacy of BRAFi is unpredictable just that intrinsic genetic complexity and partially unknown reason.Therefore, To understand co-mutation mechanism can help improve treatment and follow-up strategy. Methods: 339 Chinese CRC patients and 125 Western CRC data from the cBioPortal were included in study. Co-occurrence mutation analysis, GO and KEGG pathway enrichment analysis was enabled in this study. Results: 35/339 (10.32%) patients were BRAF mutation, with 17 patients were BRAF V600E in Beijing hospital. Patients with BRAF mutation had significantly associated with TMB-H (p = 0.0004) and MSI (p = 0.0003) than those with BRAF wild-type. In 125 BRAF mutation western cohort, The frequency clinicpathologic features, MSI, TMB, and BRAF mut-type were consistent with Chinese data. However, the primary tumor location showed significant statistical differences (P &lt; 0.0001). In Chinese cohort, class 1 (BRAF V600E , A deeper classification system of BRAF mutations) were more likely to occur in Elder, Female, western cohort was consistent with above. Other clinicpathologic features were not associated with mut-type in Chinese cohort. However, Western cohort showed class 1 exhibited primary sample type predominance(vs class NA, P &lt; 0.05; vs class 3, P &lt; 0.05). Right-sided was more likely to occur in class 1(P &lt; 0.05), this was inconsistent with the data analyzed above. Meantime, The data showed TMB-H (57.69% vs 11.76%, P &lt; 0.001) and MSI-H (28.21% vs 14.29%, P &lt; 0.005) of the class 1 were significantly higher, compared with class 3. In concurrent oncogenic mutations. Compared with non-class 1, class 1 were more likely co-passenger mutation. Data from Western populations show similar results. We also found that the class 1 was mutually exclusive with co-KRASmt in CRC, and co-APCmt appeared more frequently in non-class 1. In pathway enrichment, KEGG pathway showed that fewer proto-cancer signaling pathways were enriched in the class 1, which further confirmed that this type had stronger tumorigenicity. GO enrichment also proved that class1 had stronger tumorigenicity. Finally, Prognostic analysis showed median overall survival(OS) of 47.57 months in class 1 versus 19.43 months in non-class 1(p = 0.0002). Further study showed that the mOS of class 1/2/3/NA was 19.43 months, 28.50 months, 47.57 months and NA months(P = 0.0001), respectively. Conclusions: This study shown class 1/non-class 1 BRAF mutation in CRC have significantly differences in co-mutation features, genomic markers and prognioses. Especially, class I BRAF mutation in Chinese patients have higher TMB and MSI,maybe we could choose BRAFi and immunotherapy for them. Understanding BRAF mutation types and co-mutation mechanism will contribute to accurately grasp treatment, follow-up strategies and promote the development of precision therapy for CRC in the future.